p53 status correlates with histopathological response in patients with soft tissue sarcomas treated using isolated limb perfusion with TNF-α and melphalan

Background: Recombinant tumor necrosis factor-α (TNF-α) combined to melphalan is clinically administered through isolated limb perfusion (ILP) for regionally advanced soft tissue sarcomas of the limbs. In preclinical studies, wild-type p53 gene is involved in the regulation of cytotoxic action of TNF-α and loss of p53 function contributes to the resistance of tumour cells to TNF-α. The relationship between p53 status and response to TNF-α and melphalan in patients undergoing ILP is unknown. Patients and methods: We studied 110 cases of unresectable limbs sarcomas treated by ILP. Immunohistochemistry was carried out using DO7mAb, which reacts with an antigenic determinant from the N-terminal region of both the wild-type and mutant forms of the p53 protein, and PAb1620mAb, which reacts with the 1620 epitope characteristic of the wild-type native conformation of the p53 protein. The immunohistochemistry data were then correlated with various clinical parameters. Results: P53DO7 was found expressed at high levels in 28 patients, whereas PAb1620 was negative in 20. The tumours with poor histological response to ILP with TNF-α and melphalan showed significantly higher levels of p53-mutated protein. Conclusions: Our results might be a clue to a role of p53 protein status in TNF-α and melphalan response in clinical us

Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

Objective To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation. Methods Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018. Results Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability. Conclusions We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging

The role of genetic factors in predisposition to squamous cell cancer of the head and neck

© 1999 Cancer Research Campaig

Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas

This study sought to determine whether the presence of hypermethylated genes in the surgical margins can predict local recurrences in head and neck squamous cell carcinomas (HNSCCs). We prospectively collected tumour and surgical margin specimens from patients with HNSCCs who had undergone surgical resections. Quantitative methylation-specific PCR (QMSP) of CDKN2A, CCNA1 and DCC were performed in these specimens and correlated with clinical data. Of the 42 patients eligible for the study, 27 were hypermethylation informative for the above three genes. This latter group was associated with longer disease-free survivals (P=0.007) and longer time to disease-specific deaths (P=0.004). Multivariate analyses confirmed hypermethylation non-informative tumours as an independent prognosticating factor for disease-specific deaths (risk ratio 3.8, P=0.026). Quantitative MSP of the margins of 24 hypermethylation informative tumours revealed that 11 patients had molecularly positive margins, of which, five developed disease-specific events (DSEs, three local recurrences and two metastases), compared to none in patients with molecularly negative margins, after a median follow-up of 48 months. Log-rank analyses showed that molecularly positive margins were associated with shorter time to local recurrences and disease-specific deaths (P=0.03 and 0.01, respectively). This study demonstrated that QMSP of hypermethylated promoters in surgical margins predicted all the local recurrences in our series of HNSCC patients. We have also identified hypermethylation non-informative tumours as an independent predictor for the development of DSEs

Characteristics of Acacia mangium shoot apical meristems in natural and in vitro conditions in relation to heteroblasty

PDF version of the authors can be published in January 2013International audienceMorphological and histocytological characteristics of Acacia mangium shoot apical meristems (SAMs) were assessed in natural and in vitro conditions in relation to heteroblasty. In the natural environment, SAMs with a mature-phyllode morphology were much bigger, contained more cells with larger vacuolated area, or vacuome, and lower nucleoplasmic ratios than those from the juvenile type (Juv). In these latter, nuclei appeared more voluminous, evenly and lightly stained, with clearly distinguishable nucleolei and less abundant chromocenters. In vitro, where reversions from mature to juvenile morphological traits do occur unpredictably, heteroblasty was less obvious in the SAM characteristics examined. In vitro SAMs corresponding to the juvenile and mature types showed similarities with outdoor Juv SAMs, but could be distinguished from these latter by a much larger vacuome that might be induced by the culture conditions. These findings encourage pursuing the investigations at the chromatin and nucleolus level in SAM zones where heteroblasty-related differences have been detected

Reorientations in pivalic acid (2,2-dimethyl propanoic acid). - II. Incoherent quasielastic neutron scattering study

Rotational motions of pivalic acid are analysed in its solid plastic phase, using time of flight neutron spectroscopy. Four different partially deuterated compounds are studied, to analyse motions of the different parts of the molecule. From a study of the compound (CH3)3CCOOD, an elastic incoherent structure factor is extracted which corresponds to a model based upon uniaxial rotational diffusion of the t-butyl groups about their threefold symmetry axis, together with fluctuations of the long axes of the dimer units, about their mean direction of orientation along the [110] lattice axes. The width of the angular distribution is found equal to about 10°. A phenomenological analysis of the low-energy part of the inelastic spectra in terms of a single overdamped oscillator confirms these results, leading to a mean oscillatory amplitude of about 8°. Subtraction of the spectra obtained with the fully deuterated compound (CD3)3CCOOD, from those measured with (CD3)3CCOOH enables the study of the motion of the carboxylic group. This is found to consist of 180° jumps about the central molecular C-C bond. These results are entirely consistent with the measurements performed on the fully hydrogenated compound (CH3)3CCOOH.Nous avons étudié les mouvements de rotation de l'acide pivalique dans sa phase solide plastique, en utilisant la spectrométrie de neutrons par temps de vol. L'étude a porté sur quatre échantillons différents partiellement deutériés, afin d'analyser les mouvements respectifs des diverses parties de la molécule. En étudiant le composé (CH3)3CCOOD, nous avons pu extraire un facteur de structure élastique incohérent qui correspond à un modèle fondé sur une combinaison d'une diffusion rotationelle uniaxiale des groupements t-butyles autour de leur axe de symétrie d'ordre trois avec des fluctuations du grand axe des dimères autour de leur direction moyenne d'orientation le long des axes [110] du réseau. La largeur de la fonction de distribution est d'environ 10°. Une analyse phénoménologique de la partie basse énergie des spectres inélastiques sur la base d'un oscillateur suramorti unique confirme ces résultats, en conduisant à une amplitude moyenne de 8° environ. En soustrayant les spectres obtenus avec le composé complètement deutérié (CD3)3CCOOD de ceux mesurés avec (CD3 )3CCOOH, il est possible d'étudier le mouvement du groupement carboxylique. Celui-ci consiste en des sauts de 180° autour de la liaison moléculaire centrale C-C. Tous ces résultats sont en parfait accord avec les mesures effectuées à partir du composé complètement hydrogèné (CH3) 3CCOOH